Phase II-selective induction of hepatic drug-metabolizing enzymes by oltipraz -5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione-, 1,7-phenanthroline, and 2,2'-dipyridyl in rats is not accompanied by induction of intestinal enzymes.
The induction of hepatic and intestinal cytochrome P450, NAD(P)H:quinone oxidoreductase (QOR), glutathione S-transferase (GST), and UDP-glucuronosyltransferase (UGT) activities by intragastric administration of 1,7-phenanthroline, 2,2'-dipyridyl, and oltipraz has been investigated in rats. In the liver, all three compounds induced phase II drug-metabolizing enzymes without inducing overall cytochrome P450 concentrations and, in a direct comparison, all agents induced the enzymes to a greater extent than did the same dose of tert-butyl-4-hydroxyanisole. With a 75 mg/kg daily, 3-day regimen, UGT, GST, and QOR activities were induced by all compounds. The changes in hepatic GST, QOR, and UGT activities induced by N-heterocyclic compounds were accompanied by increases in the amounts of mRNA for GST Ya (2-2.4-fold), QOR (1.6-2.8-fold), and the UGTs UGT2B1 (4-6-fold) and UGT1A6 (4-10-fold). Changes in the amounts of UGT2B1 mRNA and UGT1A6 mRNA were highly correlated (r = 0. 9), but there was no correlation between changes in either UGT2B1 or UGT1A6 mRNA and GST Ya mRNA. No significant mRNA changes were elicited by tert-butyl-4-hydroxyanisole. Neither GST nor UGT activities were induced in the small intestinal mucosa by any agent. QOR activity was slightly induced by oltipraz. The data suggest that requirements for induction of phase II enzymes in the intestine are markedly different from requirements in the liver.
Vargas
M
M
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA.
Lamb
J G
JG
Franklin
M R
MR
D015082:2,2'-Dipyridyl / Q000494:pharmacology*; D000818:Animals; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction / Q000502:physiology*; D014453:Glucuronosyltransferase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008658:Inactivation, Metabolic / Q000502:physiology*; D007422:Intestines / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D010618:Phenanthrolines / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013871:Thiones; D013876:Thiophenes
D010618:Phenanthrolines; D011719:Pyrazines; D012333:RNA, Messenger; D013871:Thiones; D013876:Thiophenes; C053486:1,7-phenanthroline; D002083:Butylated Hydroxyanisole; D015082:2,2'-Dipyridyl; C026209:oltipraz; D003577:Cytochrome P-450 Enzyme System; D016660:NAD(P)H Dehydrogenase (Quinone); D014453:Glucuronosyltransferase; D005982:Glutathione Transferase